1. Field of the Invention
This invention relates to pyrimido[1,2-a]quinoline-2-carboxylic acids and derivatives thereof and to their use as antiallergy agents. More particularly, it relates to 1-oxo-1H-6-substitutedpyrimido[1,2-a]quinoline-2-carboxylic acids wherein the substituent is chloro, bromo, alkoxy, alkenyloxy or alkynyloxy; pharmaceutically-acceptable cationic salts thereof; and derivatives thereof such as esters and amides of the 2-carboxylic acid group, and derivatives of such compounds wherein the benzenoid ring bears one or more substituents, which are useful as agents for the treatment of allergic reactions, and especially of allergic bronchial asthma.
2. Description of the Prior Art
Allergic reactions, the symptoms resulting from an antigen antibody interaction, manifest themselves in a wide variety of ways and in diffusely different organs and tissues. One of the most disabling and debilitating of the allergic reactions is asthma, a functional condition of the bronchi characterized by periodic and spasmodic attacks of breathlessness, wheezing, coughing, and expectoration of mucous.
Efforts to discover medicinal agents to alleviate the symptoms of the abnormal physiologic state have been extensive. As early as 1910, Matthews, Brit. Med. J., 1, 441 (1910) reported the bronchodilator effects of epinephrine. Since then, Chen and Schmidt, J. Pharmacol. Exper. Therap., 24, 339 (1924) reported the use of the alkaloid ephedrine as an orally efficacious bronchodilator with the same spectrum of activity as epinephrine. In 1940, Konzett, Arch. Exp. Path. Pharmak., 197, 27 (1940) outlined the effects of the potent aerossol bronchodilator isoproterenol. Cullum et al., Brit. J. Pharmacol. Exp., 35, 141 (1969) reported the pharmacology of salbutamol, a potent bronchodilator of prolonged duration, and active via both oral and aerosol administration. Many bronchodilator preparations contain theophylline. These are generally less potent than sympathomimetic amines such as isoproterenol and salbutamol, and are ineffective in aerosol administration.
Recently, Cox and co-workers, Adv. In Drug Res., 5, 115 (19870) described the pharmacology of disodium cromoglycate [1,3-bis(2-carboxychromon-6-yloxy)-2-hydroxypropane, Intal], an agent useful in the treatment of bronchial asthma. It is not a bronchodilator but mediates its therapeutic effects by a unique mechanism of action. It suffers from the lack of oral efficacy and, for optimum results, is administered by inhalation as a solid inhalant.
Although the aforementioned agents represent outstanding contributions toward the treatment of asthma, many of them exert the undesired side effect of cardiac stimulation.
The synthesis of a 1H-pyrimido[1,2-a]quinoline appears to have first been reported by Antaki et al., J. Chem. Soc., pp. 551-555 (1951) who condensed 2-chloroquinoline with ethyl .beta.-amino crotonate in the presence of anhydrous potassium carbonate and a trace of copper bronze to produce 1-oxo-1H-3-methylpyrimido[1,2-a]quinoline. No utility for the compound was reported.
Antaki, J. Am. Chem. Soc., 80, 3066-9 (1958), reports the condensation of 2-aminoquinoline and ethylethoxymethylenecyanoacetate to give ethyl 2-quinolyaminomethylenecyanoacetate which when distilled under reduced pressure afforded 1-oxo-1H-pyrimido[1,2-a]quinoline-2-carbonitrile. The compound demonstrated antischistosomal action.
The synthesis of a series of 1-oxo-1H-pyrimido[1,2-a]benzimidazole-2-carboxylic acids and esters is reported by Dunwell et al., J. Chem. Soc. (Perkin I), No. 15, 1588-1590 (1973), and by Chow et al., J. Hetero. Chem., 10, 71-75 (1973). No reference to the utility of the compounds is presented.
A representative compound of the above series of compounds; namely, ethyl 1-oxo-1H-pyrimido[1,2-a]benzimidazole-2-carboxylate, when tested for antiallergy activity by the passive cutaneous anaphylaxis (PCA) test (Ovary, J. Immun., 81, 355, 1958) described below, was found to be inactive.
Richardson et al., J. Med. Chem., 15, 1203-6 (1972) describe ethyl 1-oxo-1H-pyrimido[1,2-a]quinoline-2-carboxylate and report it to be inactive as an antimicrobial agent. When tested for antiallergy activity by the PCA test it was found to exhibit 100% inhibition at 3 mg./kg. by the intravenous (I.V.) route of administration but is without activity at 1 mg./kg. I.V. Approximately 90% inhibition is demonstrated at 30 mg./kg. by the oral route of administration, but oral activity is absent at a dosage level of 10 mg./kg. via the oral route.
Gupta et al., Indian J. Chem., 9, 201-206 (1971) report the preparation of a compound identified as ethyl 1-oxo-1H-6-hydroxypyrimido[1,2-a]quinoline-2-carboxylate and its investigation as a hypoglycemic agent. The corresponding acid, 1-oxo-1H-6-hydroxpyrimido[1,2-a]quinoline-2-carboxylic acid, when tested for antiallergy activity by the PCA test, exhibited 83% inhibition at 30 mg./kg. I.V. and 8% exhibition at 3 mg./kg. I.V. No activity was exhibited by the oral route of administration at 3 mg./kg.
The 6-chloro analog, ethyl 1-oxo-1H-6-chloropyrimido[1,2-a]quinoline-2-carboxylate, when tested by the PCA test, was found to exhibit 82% and 19% inhibition at 3 mg./kg. and 1 mg./kg., respectively, via the I.V. route of administration. No practical oral activity was exhibited at 30 mg./kg.